antipsychotic agents by s.bohlooli phd school of medicine, ardabil university of medical sciences
TRANSCRIPT
Neuroleptic: synonym for antipsychotic drug; originally indicated drug with antipsychotic efficacy but also neurologic (extrapyramidal motor) side effects, now claimed as subtype of antipsychotic drugs
Typical neuroleptic: older agents fitting this description
atypical" antipsychotic : newer agents: antipsychotic efficacy with reduced or no neurologic side effects
Introduction
Reserpine Chlorpromazine: neuroleptic agent The discovery of clozapine was in 1959
antipsychotic drugs need not cause EPS
History
The presence of delusions (false beliefs) Various types of hallucinations, usually
auditory or visual, but sometimes tactile or olfactory
Disorganized thinking in a clear sensorium
Nature of Psychosis & Schizophrenia
Hallucinogens such as LSD (lysergic acid diethylamide) and mescaline are serotonin (5-HT) agonists
5-HT2A-receptor blockade is a key factor in the mechanism of action of the main class of atypical antipsychotic drugs such as clozapine and quetiapine.
5-HT2C-receptor stimulation provides a further means of modulating
The Serotonin Hypothesis of Schizophrenia
Was the first neurotransmitter-based concept Excessive limbic dopaminergic activity plays a role in
psychosis Many antipsychotic drugs strongly block postsynaptic D2
receptors: Includes partial dopamine agonists, such as aripiprazole and
bifeprunox Drugs that increase dopaminergic activity either aggravate
schizophrenia psychosis or produce psychosis de novo Dopamine-receptor density is high postmortem
The atypical antipsychotic drugs Much less effect on D2 receptors Role of other dopamine receptors and to nondopamine receptors
The Dopamine Hypothesis of Schizophrenia
Glutamate is the major excitatory neurotransmitter in the brain
Phencyclidine and ketamine are noncompetitive inhibitors of the NMDA receptor
Hypofunction of NMDA receptors, located on GABAergic interneurons
The Glutamate Hypothesis of Schizophrenia
Antipsychotic Drugs: Relation of Chemical Structure to Potency and Toxicities
Chemical Class
Drug D2/5-HT2A
Ratio1
Clinical Potency
Extrapyramidal Toxicity
Sedative Action
Hypotensive Actions
Phenothiazines
Aliphatic Chlorpromazine High Low Medium High High
Piperazine Fluphenazine High High High Low Very low
Thioxanthene Thiothixene Very high High Medium Medium Medium
Butyrophenone
Haloperidol Medium High Very high Low Very low
Dibenzodiazepine
Clozapine Very low Medium Very low Low Medium
Benzisoxazole Risperidone Very low High Low2
Low Low
Thienobenzodiazepine
Olanzapine Low High Very Low Medium Low
Dibenzothiazepine
Quetiapine Low Low Very Low Medium Low to Medium
Dihydroindolone
Ziprasidone Low Medium Very Low Low Very Low
Dihydrocarbostyril
Aripiprazole Medium High Very Low Very Low Low
Absorption and Distribution Readily but incompletely absorbed Significant first-pass metabolism Highly lipid-soluble and protein-bound
Metabolism Almost completely metabolized Drug-drug interactions should be considered
Pharmacokinetics
All neuroleptics are equally effective in treating psychoses, including schizophrenia, but differ in their tolerability.
All neuroleptics block one or more types of DOPAMINE receptor, but
differ in their other neurochemical effects. show a significant delay before they become effective. produce significant adverse effects.
KEY CONCEPTS:
The older, typical neuroleptics are effective antipsychotic agents with neurologic side effects involving the extrapyramidal motor system.
Typical neuroleptics block the dopamine-2 receptor.
GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS
Typical neuroleptics do not produce a general depression of the CNS, e.g. respiratory depression
Abuse, addiction, physical dependence do not develop to typical neuroleptics.
GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS
Typical neuroleptics are generally more effective against positive (active) symptoms of schizophrenia than the negative (passive) symptoms.
GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS
Positive/active symptoms include thought disturbances, delusions, hallucinations
Negative/passive symptoms include social withdrawal, loss of drive, diminished affect, paucity of speech, impaired personal hygiene
All appear equally effective; choice usually based on tolerability of side effects
Most common are haloperidol ,chlorpromazine and thioridazine
Latency to beneficial effects; 4-6 week delay until full response is common
70-80% of patients respond, but 30-40% show only partial response
THERAPEUTIC EFFECTS OF TYPICAL NEUROLEPTICS
Relapse, recurrence of symptoms is common ( approx. 50% within two years).
Noncompliance is common.
Adverse effects are common.
THERAPEUTIC EFFECTS OF TYPICAL NEUROLEPTICS (Continued)
Anticholinergic (antimuscarinic) side effects: Dry mouth, blurred vision, tachycardia,
constipation, urinary retention, impotence Antiadrenergic (Alpha-1) side effects:
Orthostatic hypotension , reflex tachycardia
Sedation Antihistamine effect: sedation, weight gain
ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS
DYSTONIA NEUROLEPTIC MALIGNANT SYNDROME PARKINSONISM TARDIVE DYSKINESIA AKATHISIA
KEY CONCEPT: DOPAMINE-2 RECEPTOR BLOCKADE IN THE BASAL GANGLIA RESULTS IN EXTRAPYRAMIDAL MOTOR SIDE EFFECTS (EPS).
Increased prolactin secretion (common with all; from dopamine blockade)
Weight gain (common, antihistamine effect?) Photosensitivity (v. common w/ phenothiazines) Lowered seizure threshold (common with all) Leukopenia , agranulocytosis (rare; w/
phenothiazines) Retinal pigmentopathy (rare; w/ phenothiazines)
ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS (Continued)
Chlorpromazine and thioridazine produce marked autonomic side effects and sedation; EPS tend to be weak (thioridazine) or moderate (chlorpromazine).
Haloperidol, thiothixene and fluphenazine produce weak autonomic and sedative effects, but EPS are marked.
ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS (Continued)
DOPAMINE-2 receptor blockade in meso-limbic and meso-cortical systems for antipsychotic effect.
DOPAMINE-2 receptor blockade in basal ganglia (nigro-striatal system) for EPS
DOPAMINE-2 receptor supersensitivity in nigrostriatal system for tardive dyskinesia
MECHANISMS OF ACTION OF TYPICAL NEUROLEPTICS and Some
Side Effects
Dopamine neurons reduce activity. Postsynaptic D-2 receptor numbers increase
(compensatory response). When D2 blockade is reduced, DA neurons resume
firing and stimulate increased # of receptors >> hyper-dopamine state >> tardive dyskinesia
LONG TERM EFFECTS OF D2 RECEPTOR BLOCKADE:
Dystonia and parkinsonism: anticholinergic antiparkinson drugs
Neuroleptic malignant syndrome: muscle relaxants, DA agonists, supportive
Akathisia: benzodiazepines, propranolol Tardive dyskinesia: increase neuroleptic dose; switch
to clozapine
MANAGEMENT OF EPS
Adjunctive in acute manic episode Tourette’s syndrome (Haloperidole ) Control of psychosis in depressed patient Phenothiazines are effective anti-emetics,
Esp. prochlorperazine Also, anti-migraine effect
ADDITIONAL CLINICAL USES OF TYPICAL NEUROLEPTICS
Differences among Antipsychotic Drugs
Chlorpromazine: 1 = 5-HT2A > D2 > D1
Haloperidol: D2 > 1 > D4 > 5-HT2A > D1 > H1
Clozapine: D4 = 1 > 5-HT2A > D2 = D1
Olanzapine: 5-HT2A > H1 > D4 > D2 > 1 > D1
Aripiprazole: D2 = 5-HT2A > D4 > 1 = H1 >> D1
Quetiapine: H1 > 1 > M1,3 > D2 > 5-HT2A
Effective antipsychotic agents with greatly reduced or absent EPS, esp. reduced Parkinsonism and tardive dyskinesia
All atypical neuroleptics block dopamine and serotonin receptors; other neurochemical effects differ
Are effective against positive and negative symptoms of schizophrenia; and in patients refractory to typical neuroleptics
GENERAL CHARACTERISTICS OF ATYPICAL
Antipsychotic
Combination of Dopamine-4 and Serotonin-2 receptor blockade in cortical and limbic areas for the “pines” like clozapine
Combination of Dopamine-2 and Serotonin-2 receptor blockade (esp. risperidone)
HYPOTHESIZED MECHANISMS OF ACTION OF ATYPICAL NEUROLEPTICS
FDA-approved for patients not responding to other agents or with severe tardive dyskinesia
Effective against negative symptoms Also effective in bipolar disorder Little or no parkinsonism, tardive dyskinesia, PRL
elevation, neuro-malignant syndrome; some akathisia
PHARMACOLOGY OF CLOZAPINE
Other adverse effects;
Weight gain Increased salivation Increased risk of seizures Risk of agranulocytosis requires
continual monitoring
PHARMACOLOGY OF CLOZAPINE (Continued )
Olanzapine is clozapine without the agranulocytosis.
Same therapeutic effectiveness Same side effect profile
PHARMACOLOGY OF OLANZAPINE
Quetiapine is olanzapine without the anticholinergic effects.
Same therapeutic effectiveness Same side effect profile
PHARMACOLOGY OF QUETIAPINE
Highly effective against positive and negative symptoms Adverse effects:
EPS incidence is dose-related Alpha-1 receptor blockade Little or no anticholinergic or
antihistamine effects Weight gain, PRL elevation
Resperidone
Adverse Pharmacologic Effects of Antipsychotic Drugs
Type Manifestations Mechanism
Autonomic nervous system
Loss of accommodation, dry mouth, difficulty urinating, constipation
Muscarinic cholinoceptor blockade
Orthostatic hypotension, impotence, failure to ejaculate
Adrenoceptor blockade
Central nervous system Parkinson's syndrome, akathisia, dystonias
Dopamine-receptor blockade
Tardivedyskinesia Supersensitivity of dopamine receptors
Toxic-confusional state Muscarinic blockade
Endocrine system Amenorrhea-galactorrhea, infertility, impotence
Dopamine-receptor blockade resulting in hyperprolactinemia
Other Weight gain Possibly combined H1 and 5-
HT2 blockade
Use typical for:
1st acute episode w/ + or +/- symptoms
Switch to atypical if:
Breakthrough after Rx w/ typical Use typical (depot prep) when:
Patient is noncompliant
General Therapeutic Principles for Use of Neuroleptics in Schizophrenia
(NIH Consensus Statement, 1999)